Diabetic complications, including diabetic retinopathy, nephropathy, and neuropathy are largely the result of abnormalities in microvascular function. Changes in vascular function include increased blood vessel permeability and altered blood flow. These changes precede the development of the clinical symptoms of diabetic complications.
Diabetic retinopathy and proliferative vitreoretinopathy are characterized by the growth of new blood vessels, or angiogenesis. One of the early events in angiogenesis is secretion of proteases involved in the dissolution of the basement membrane. These proteases include the plasminogen activators, procollagenase and prostromelysin. Plasminogen activators such as urokinase (uPA) and tissue plasminogen activator (tPA) are serine proteases which cleave the zymogen plasminogen to generate the active serine protease plasmin. Plasmin can influence basement membrane integrity directly through cleavage of basement membrane components or indirectly through cleavage of procollagenase and prostromelysin to generate active collagenase and stromelysin. The resulting dissolution of the basement membrane allows the endothelial cells to escape from the microvessel and begin the neovascularization process.
Increased plasmin formation also has several ramifications in terms of the permeability of the diabetic microvessel. Plasmin can directly degrade basement membrane components or can activate stromelysin, thus directly or indirectly influencing the normal turnover of heparan sulfate proteoglycan (HSPG). Because HSPG is involved in blood vessel permeability as well as growth control, this enhanced degradation of HSPG may result in its depletion from the membrane with resultant increased vessel permeability.
Microvascular dysfunctions arise through this abnormal activation of endothelial cells which is mediated, in part, through protein kinase C (PKC)-regulated pathways. See MacGregor, et al., J Clin Invest, 83: 90-94 (1988); Lee, et al., Proc. Natl. Acad. Sci., 85: 5141-5145 (1989).
Agents that block or reverse the activation of endothelial cells and inhibit the alterations in microvessel function will have a beneficial effect in terms of preserving normal structure and function in the tissues affected by the complications of diabetes. The agents will improve the quality of life and longevity of diabetics.
The present invention discloses a method of inhibiting endothelial cell activation. Accordingly, the present invention provides a method of treating diabetic complications in mammals which comprises the administration of a compound of the Formula I: ##STR2## This invention covers the use of these compounds in the treatment of diabetic complications, as well as in other disease states in which there is vascular dysfunction.